In recent years, there have been intense exploration and study of bioactive substances derived from the sea. Among these, useful substances holding forth promise as pharmaceuticals and lead compounds for pharmaceuticals have been discovered. For example, hymenialdisine and debromohymenialdisine have been isolated from sponges.
For example, hymenialdisine has been isolated from Axinella verrucosa, Acanthella aurantiaca (Cimino, G. et al: Tetrahedron Lett., 23, 767 (1982)), Hymeniacidon aldis (Kitagawa, I. et al: Chem. Pharm. Bull., 31, 2321 (1983)), and an unconfirmed Kololevu sponge (Schmitz, F. et al: J. Nat. Prod., 48, 47 (1985)), while debromohymenialdisine has been isolated from Phakellia flabellata (Sharma, G. et al: J. Chem. Soc., Chem. Commun., 435 (1980)) and Hymeniacidon aldis (Kitagawa, I. et al: Chem. Pharm. Bull., 31, 2321 (1983); Endo, M. et al: Pure & Appl. Chem., 58, 387 (1986)).
In the above formula (I), the compound having an X.sup.1 of a bromine atom is hymenialdisine, while the compound having an X.sup.1 of a hydrogen atom is debromohymenialdisine. These compounds have interesting biological activities.
Hymenialdisine and debromohymenialdisine are known to have antineoplastic activities (Pettit, G. et al: Can. J. Chem., 68, 1621 (1990)). Furthermore, debromohymenialdisine is known to have .alpha.-adrenoceptor blocking effect (Kobayashi, J. et al: Experimentia., 44, 86 (1988)).
Recently, it has been shown that hymenialdisine and debromohymenialdisine have an inhibitory action against protein phosphokinases, in particular, protein kinase C (Nishizuka, Y.: Nature, 334, 661 (1988); idem, JAMA, 262, 1826 (1989)), which plays an important role in cellular signal transduction (Nambi, P. et al: International Disclosure W093/16703). They are expected to have applications as drugs for the alleviation and treatment of conditions believed to involve the activation of protein kinase C, for example, cerebral ischemic disorders, cerebral vasospasm, ischemic cardiac diseases, high blood pressure, arteriosclerosis, inflammation, asthma, kidney disorders, rheumatoid arthritus, and sthenia of immunofunctions.
Hymenialdisine and debromohymenialdisine, however, can only be obtained in minute quantities when extracted and isolated from nature, so there has been a strong demand for the development of an efficient process of production enabling economical mass production of hymenialdisine and its derivatives. Such a technique, however, has not yet been known. There has just been a few studies on conversion from aldisin. Even these have not given satisfactory results. Complete synthesis is not yet achieved (Prager, R. et al: Aust. J. Chem., 43, 367 (1990); idem, ibid. 45, 1771 (1992)).